PDK1-dependent activation of atypical PKC leads to degradation of the p21 tumour modifier protein

Mary T Scott, Angela Ingram, Kathryn L Ball

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

p21(WAF1/CIP1) Contributes to positive and negative growth control on multiple levels. We previously mapped phosphorylation sites within the C-terminal domain of p21 that regulate proliferating cell nuclear antigen binding. In the current study, a kinase has been fractionated from mammalian cells that stoichiometrically phosphorylates p21 at the Ser146 site, and the enzyme has been identified as an insulin-responsive atypical protein kinase C (aPKC). Expression of PKCzeta or activation of the endogenous kinase by 3-phosphoinositide dependent protein kinase-1 (PDK1) decreased the half-life of p21. Conversely, dnPKCzeta or dnPDK1 increased p21 protein half-life, and a PDK1-dependent increase in the rate of p21 degradation was mediated by aPKC. Insulin stimulation gave a biphasic response with a rapid transient decrease in p21 protein levels during the initial signalling phase that was dependent on phosphatidylinositol 3- kinase, PKC and proteasome activity. Thus, aPKC provides a physiological signal for the degradation of p21. The rapid degradation of p21 protein during the signalling phase of insulin stimulation identifies a novel link between energy metabolism and a key modulator of cell cycle progression.
Original languageEnglish
Pages (from-to)6771-80
Number of pages10
JournalEMBO Journal
Issue number24
Publication statusPublished - 16 Dec 2002

Keywords / Materials (for Non-textual outputs)

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Cell Division
  • Cell Line
  • Chromatography, Gel
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Insulin
  • Peptides
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Kinase C
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Recombinant Proteins
  • Serine
  • Signal Transduction
  • Time Factors
  • Transfection


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